The finding of a genetic predisposition to Wernicke-Korsakoff syndrome in four patients will be extended and its clinical significance and molecular basis determined. Cultured skin fibroblasts and red blood cells will be obtained from 16 patients with classical Wernicke-Korsakoff syndrome (opthalmoplegia, ataxia, altered state of consciousness, response to thiamine, and persistent memory defect) and as many of their blood relations as possible. Cultured fibroblasts will also be obtained from 16 alcoholic and 16 non-alcoholic controls, matched to the patients for age, sex, and race. The alcoholic controls will include eight with diets as deficient in thiamine as those of the patients and with peripheral neuropathy but not Wernicke-Korsakoff. The non-alcoholic controls will include eight with dementia Red cells will be obtained from 100 alcoholic and 100 non-alcoholic controls including the matched controls. The Km of binding of thiamine pyrophosphate to transketolase, which was found to be abnormal in the four patients with Wernicke-Korsakoff syndrome who have been studied so far (1), will be determined in all these cells. Other kinetic properties (including heat sensitivity, dependence on pH and ionic strength, and sensitivity to inhibitors will be compared for "high Km" and "low Km" forms of the enzyme. These studies will determine the (1) frequency of the inherited abnormality in transketolase in a larger series of American patients with Wernicke-Korsakoff syndrome; (2) the pattern of inheritance; and (3) whether the abnormality in transketolase is associated with Wernicke-Korsakoff syndrome, alcoholism per se, or with dementia. Methods will be developed to purify transketolase from human red cells. Pure enzyme from patients and controls will be compared electrophoretically, immunologically and kinetically, including detailed study of the binding of thiamine pyrophosphate. These studies will clarify the molecular basis of the abnormality. These studies are expected to lead to others which exploit the fibroblast technique to identify, on a molecular level, genetic factors in alcoholism and its complications.